A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid cells. Integration is believed to occur in three stages: cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site; repair synthesis by host enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame Ratner, L. et al., Nature, 313, 277(1985)!. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an integrase and an HIV protease Toh, H. et al., EMBO J. 4,1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329,351 (1987)!.
It is known that some antiviral compounds act as inhibitors of HIV and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase, probably by inhibiting catalysis rather than preventing assembly. The particular advantage of the present invention is highly specific inhibition of HIV integrase. The compounds of the present do not inhibit a variety of other protein-nucleic acid interactions, including enzymatic reactions involving HIV reverse transriptase, DNase I, Eco RI endonuclease, or mammalian polymerase II, as well as other related interaction, e.g., involving HIV TAT protein.
Vejdelek et al., "Potential Anxiolytics and Hypnotics: 1-(Alkanesulfonamidoalkyl)-6-aryl-8-halogeno-s-triazolo4,3-a!-1,4-benzodi azepines and related compound," Collection Czechoslovak Chem. Commun. 53:132-144 (1987), describe the following compound of structural formula IA:
______________________________________ 1 #STR1## Compound R.sub.1 R.sub.2 ______________________________________ 1 Cl 2 #STR2## 2 Br 2 #STR3## 3 Cl 3 #STR4## ______________________________________
as useful in intermediates in making the psychoactive drugs of structural formula IIA: ##STR5##